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Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats

Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [(14)C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins wa...

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Autores principales: Brunner, Valérie, Maynadier, Bernadette, Chen, Laishun, Roques, Louise, Hude, Isabelle, Séguier, Sébastien, Barthe, Laurence, Hermann, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484650/
https://www.ncbi.nlm.nih.gov/pubmed/26150694
http://dx.doi.org/10.2147/DDDT.S80886
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author Brunner, Valérie
Maynadier, Bernadette
Chen, Laishun
Roques, Louise
Hude, Isabelle
Séguier, Sébastien
Barthe, Laurence
Hermann, Philippe
author_facet Brunner, Valérie
Maynadier, Bernadette
Chen, Laishun
Roques, Louise
Hude, Isabelle
Séguier, Sébastien
Barthe, Laurence
Hermann, Philippe
author_sort Brunner, Valérie
collection PubMed
description Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [(14)C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all species. Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.3%, 7.5%, and 5.6%, respectively. Similar results were seen in monkeys. N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats. Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively. N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.9% of administered dose, respectively). Human and monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively) and N-desethyl levomilnacipran glucuronide (3.2% and 2.3% of administered dose, respectively); these metabolites were not detected in rat urine. The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤1.2% of administered dose), and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose). None of the metabolites were pharmacologically active. Levomilnacipran was widely distributed with low plasma protein binding (22%).
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spelling pubmed-44846502015-07-06 Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats Brunner, Valérie Maynadier, Bernadette Chen, Laishun Roques, Louise Hude, Isabelle Séguier, Sébastien Barthe, Laurence Hermann, Philippe Drug Des Devel Ther Original Research Levomilnacipran is approved in the US for the treatment of major depressive disorder in adults. We characterized the metabolic profile of levomilnacipran in humans, monkeys, and rats after oral administration of [(14)C]-levomilnacipran. In vitro binding of levomilnacipran to human plasma proteins was also studied. Unchanged levomilnacipran was the major circulating compound after dosing in all species. Within 12 hours of dosing in humans, levomilnacipran accounted for 52.9% of total plasma radioactivity; the circulating metabolites N-desethyl levomilnacipran N-carbamoyl glucuronide, N-desethyl levomilnacipran, and levomilnacipran N-carbamoyl glucuronide accounted for 11.3%, 7.5%, and 5.6%, respectively. Similar results were seen in monkeys. N-Desethyl levomilnacipran and p-hydroxy levomilnacipran were the main circulating metabolites in rats. Mass balance results indicated that renal excretion was the major route of elimination with 58.4%, 35.5%, and 40.2% of total radioactivity being excreted as unchanged levomilnacipran in humans, monkeys, and rats, respectively. N-Desethyl levomilnacipran was detected in human, monkey, and rat urine (18.2%, 12.4%, and 7.9% of administered dose, respectively). Human and monkey urine contained measurable quantities of levomilnacipran glucuronide (3.8% and 4.1% of administered dose, respectively) and N-desethyl levomilnacipran glucuronide (3.2% and 2.3% of administered dose, respectively); these metabolites were not detected in rat urine. The metabolites p-hydroxy levomilnacipran and p-hydroxy levomilnacipran glucuronide were detected in human urine (≤1.2% of administered dose), and p-hydroxy levomilnacipran glucuronide was found in rat urine (4% of administered dose). None of the metabolites were pharmacologically active. Levomilnacipran was widely distributed with low plasma protein binding (22%). Dove Medical Press 2015-06-23 /pmc/articles/PMC4484650/ /pubmed/26150694 http://dx.doi.org/10.2147/DDDT.S80886 Text en © 2015 Brunner et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Brunner, Valérie
Maynadier, Bernadette
Chen, Laishun
Roques, Louise
Hude, Isabelle
Séguier, Sébastien
Barthe, Laurence
Hermann, Philippe
Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title_full Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title_fullStr Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title_full_unstemmed Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title_short Disposition and metabolism of [(14)C]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
title_sort disposition and metabolism of [(14)c]-levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, in humans, monkeys, and rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4484650/
https://www.ncbi.nlm.nih.gov/pubmed/26150694
http://dx.doi.org/10.2147/DDDT.S80886
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